Biologically active 17alpha-ethynyl-16,17-dihydroxy-13-alkygonanes

ABSTRACT

13 - ALKYL - 16A,17B - DIHYDROXY-GON-4-ENE-3-ONE COMPOUNDS ARE CONVERTED IN 13-ALKYL-16A, 17B-DIHYDROXY-17ETHYNYL GONANE AND 13-ALKYL-16B,17B-DIHYDROXY GONANE COMPOUNDS HAVING PROGESTATIONAL AND ANTI-ESTROGENIC ACTIVITY.

United States Patent 3,734,935 BIOLOGICALLY ACTIVE 17a-ETHYNYL-16,17-DIHYDROXY-13-ALKYGONANES George E. M. Husbands, Philadelphia, andReinhardt P. Stein, Audubon, Pa., assignors to American Home ProductsCorporation, New York, N.Y. No Drawing. Filed July 21, 1972, Ser. No.274,004 Int. Cl. C07c 169/22 US. Cl. 260-3974 1 Claim ABSTRACT OF THEDISCLOSURE 13 alkyl 1611,17}? dihydroxy-gon-4-ene-3-one compounds areconverted to 13-alkyl-16a,17fl-dihydroxy-17- ethynyl gonane andl3-alkyl-16;8,17-;8-dihydroxy gonane compounds having progestational andanti-estrogenic activity.

DESCRIPTION OF THE INVENTION The invention sought to be patented residesin the con cept of a compound of the structure ---CECH TOE wherein R isalkyl of from 1 to 4 carbon atoms; and X is C=O,

DESCRIPTION OF THE PREFERRED EMBODIMENTS Although, for convenience, thefollowing discussion will describe the preparation of the compounds ofthe invention by reference to a particular embodiment thereof wherein -Ris ethyl, it is to be understood that this discussion is equallyapplicable to all of the embodiments of the invention.

Referring to the following flow chart wherein the compounds are assignedRoman numerals for purposes of identification, the starting material,16a,17B-dihydroxy- 13-ethylgon-4en-3-one (XV-I) may be prepared by meansknown in the art. Thus it may be prepared from the known compound,13-ethyl-3-methoxygona- 1,3,5 )-I'i6116-16u- 17/8-diol (British Pat.1,115,954) by reduction with lithium metal and ammonia under Birchconditions followed by acid hydrolysis. Catalytic reduction of XVI, forexample with hydrogen and 10% palladium on carbon atfords the5/3-saturated A-ring compound (1); reduction of XVI with lithium metalin ammonia gives the corresponding 5acompound (11). Further treatment ofI and II to produce the corresponding 511- and 5,8-compounds of theinvention is identical, so for convenience they are depicted toicegether as Formula III. The subsequent discussion thus applies to bothepimeric forms. After protection of III as the ketal (IV), for exampleby treatment with ethylene glycol, triethyl orthoformate andp-toluenesulfonic acid, the latter compound is selectively formylatedwith dimethyl formamide and methane sulfonyl chloride to afford the16-formyl compound V. Oxidation of V, for exampledimethyl-sulfoJdde-acetic anhydride, or chromium trioxide in pyridineaffords the corresponding 17-ketone (VI). Treatment of V1 with ethynylGrignard reagent,

OH OH Et Et -OH --OH (XVI) (I) (III) Et --OH [O W OCHO :0

--ocrro El agon M05011 "OH --OH VII (VII on on El "-0501; Et

OH --OH HO- no (IX) (X) for example ethynylmagnesium bromide intetrahydrofuran alfords the 16a-hydroxy-l7a-ethynyl-l7fi-hydroxycompound VII which upon acid hydrolysis, for example with aqueoushydrochloric acid in methanol affords the 3-one compound of theinvention VIII. Reduction of VIII, for example with sodium borohydridein methanol, affords a mixture of the 3a-hydroxy and Sfi-hydroxycompounds of the invention (IX) and (X), These latter compounds may beseparated by various methods known to those skilled in the art, such aschromatography, for example on silica gel with benzene.

The synthesis of the l6 8-hydroxy compounds of the invention is depictedin the following flow chart. Hydrolysis of VI with methanolic sodiumhydroxide at low temperature affords the corresponding 16u-hydroxycompound XI. Treatment of XI with dihydropyran and ptoluenesulfonic acidin tetrahydrofuran aifords the 160:- tetrahydropyranyloxy compound (XII)which upon treatment with lithium acetylide-ethylene diamine complex indimethylsulfoxide/ benzene, followed by acid hydrolysis of theprotecting groups, for example with aqueous hydrochloric acid inmethanol, afiords the 16,8,17B-dihydroxy-17a-ethynyl-gonan-3-onecompound of the invention (XIII). Reduction of XIII, for example withsodium borohydride in methanol, alfords a mixture of the Bot-hydroxy and3B-hydroxy compounds of the invention (XIV) and (XV). These may beseparated as described previously for D( and X.

In employing the compounds of the invention to produce a progestationaland anti-estrogenic effect, the compounds may be administered by eitherthe oral or parenteral routes. The amount of compound to be administeredwill vary depending on the route of administration, the particularcompound employed, the

--OCHO on OH El 0501; Et "05011 HO-- HO\/ (XIV) (XV) the particularanimal involved, and the degree of response desired. Ideally, the dosageshould be individualized in each case. Generally, a dose of 5 mg./kg.body weight will be sufficient to produce the desired progestational andanti-estrogenic eflFects.

The following examples further illustrate the best mode contemplated bythe inventors of carrying out their invention:

EXAMPLE 1 Add a solution of dl-16a,17;8-dihydroxy-13-ethylgon-4-en-3-one (8.0 g.) in ethanol (200 ml.) to a prehydrogenated mixture ofpalladium on charcoal (2.0 g.), potassium hydroxide (2.5 g.) and ethanol(100 ml.). Hydrogenate until one molar equivalent of gas is absorbed.Filter, concentrate the solution, and partition the concentrate betweenwater and methylene chloride. Dry the methylene chloride solution withsodium sulfate and evaporate the extract in vacuo. Crystallize thecompound from ethyl acetate-methanol to get 4.5 g. of pure titleproduct, M.P. 210-212".

EXAMPLE 2 dl-16a,17,8-dihydroxy-13-ethy1-5a-gon-3-one Add lithium metal(0.108 g.) to a mixture of liquid ammonia (66 ml.), dry toluene ml.) anddry tetrahydrofuran (20 ml.) in a flask equipped with a magnetic stirrerand a Dry-Ice condenser. Slowly add a solution of dl-16a,l7,B-dihydroxy13 ethylgon-4-en-3-one (1.06 g.) in dry toluene (20 ml.) and drytetrahydrofuran 20 ml.). If the blue color of the lithium-liquid ammoniasolution is prematurely discharged, add more lithium to restore it. Stirthe reaction mixture for three minutes after addition of the startingcompound. Add ethylene dibromide dropwise until the blue colordisappears. Then add very cautiously a mixture of glacial acetic acid (2ml.) and methanol (8 ml.). Evaporate the ammonia. Remove the solvents invacuo. Partition the residual oil between water and ethyl acetate. Washthe ethyl acetate extract with water and brine, dry over sodium sulfate,concentrate the solution and crystallize the title compound fromisopropanol-ethyl acetate to get 750 mg., M.P. 174-176.

'EXAMPLE 3 dl-3,3-ethylenedioxy-13-ethyl-5fi-gona-16a,17}8-dio1 Add amixture of ethylene glycol (2.0 ml.), triethyl orthoformate (5.0 ml.)and paratoluene sulfonic acid (50.0 mg.) to dl-l6a,173-dihydroxy-13-ethyl-5B-gon-3-one and reflux the mixture with stirringon an oil bath (125- 135 C. external temperature) for one hour. Pour themixture into sodium bicarbonate solution (200 ml.) and extract withethyl acetate. Wash the extract with water and brine, dry over sodiumsulfate and evaporate in vacuo to obtain the title compound as a lightyellow oil.

For the substrate in the above experiment, substitutedl-16a,17;3-dihydroxy 13 ethyl 5a gon-3-one to obtain also as a yellowoil, dl-3,3-ethyleue-dioxy-13-ethyl- 5a-gona-16m,17p-diol.

EXAMPLE 4 dl-3,3-ethylenedioxy-13-ethyl-5/3-gona-16a,17pdiol, 16-formateCool spectroscopically pure dimethyl formamide (15 ml.) in anice-methanol bath and add methanesulfonyl chloride (3 ml.) dropwise. Addthis mixture to the sample of dl-3,3-ethylenedioxy 13ethyl-5fl-gona-16a,17/8- diol obtained in Example 3 and stir for onehour at room temperature. Pour into a mixture of pyridine (6 ml.) andice (large excess). Stir the mixture at room temperature for one hour.Extract with ethyl acetate, wash with water and brine and dry oversodium sulfate. Evaporate in vacuo to obtain the title product as anoil.

For the substrate in the above experiment, substitute dl 3,3ethylenedioxy-13-ethyl-5u-gona-16u,17B-diol to obtain dl 3,3ethylenedioxy-IB-ethyI-Sa-gona-1611,175- diol, 16-formate as acrystalline solid, M.P. 189-192.

EXAMPLE 5 dl-3,3-ethylenedioxy-l6a-hydroxy-13-ethyl-513-gon- 17-one,formate Dissolve dl 3,3 ethylenedioxy 13 ethyl-Sfl-gona- 160:,17B-di0l,16-formate in dimethylsulfoxide ml.) and acetic anhydride (6 ml.) andstir for 24 hours. Add saturated sodium bicarbonate and stir for a fewminutes. Extract with ethyl acetate. Wash the extract with water andbrine, dry over sodium sulfate and evaporate in vacuo to obtain thetitle product as an oil which crystallizes with difliculty, M.P. 125-128C., from isopropanol-petroleum ether.

For the substrate in the above reaction, substitute dl- 3,3ethylenedioxy 13 ethy1-5u-gona-16a,17/3-diol, 16- formate to obtaindl-3,3-ethylenedioxy-16a-hydroxy-13- ethyl-5a-gon-17-one, formate.

EXAMPLE 6 dl-3,3-ethylenedioxy-16a-hydroxy-l3-ethyl-5 3-gon- 17-one,formate Add pyridine (150 ml.) to methylene chloride (1500 ml.) and stirwell. Add chromium trioxide (20 g.) in small portions to the solventmixture and stir for a further 15 minutes after addition. To thatburgundy colored solution, add a solution ofdl-3,3-ethylenedioxy-l3-ethyl-5B- gona-16a,17,B-diol, 16-formate (11 g.)in methylene chloride rapidly dropwise and stir for minutes. Filter,wash the residue with ethyl acetate. Add water to the organic layer andextract with ethyl acetate to obtain a methylene chloride-ethyl acetateextract. Wash the extract with water and brine, dry over sodium sulfateand evaporate in vacuo. Dissolve the foam obtained in ethyl acetate,treat with activated charcoal, filter and dry the solution over sodiumsulfate. Crystallize the product from ethyl acetate to obtain 9.2 g.,M.P. -115 C.

For the substrate in the above experiment, substitute dl- 3,3 ethylenedioxy 13 -ethyl-5a-gona-16a,17fi-diol, 16- formate to obtaindl-3,3-ethylenedioxy-16a-hydroxy-13- ethyl-5u-gon-17-one, formate as acrystalline product from ethyl acetate, M.P. 201-205 C.

EXAMPLE 7 dl-3,3-ethylenedioxy-13-ethyl-17u-ethynyl-5 8-gona-16u,17,8-diol Equip a flask with a magnetic stirrer, condenser, and agas inlet tube. Charge the flask with dry tetrahydrofuran ('65 ml.) and3 M ethereal methyl magnesium bromide (30 ml.). Bubble purifiedacetylene through the stirred solution for 2.5 hours, then adddl-3,3-ethylenedioxy-l6ahydroxy-l3-ethyl-5fi-gon-17-one, formate (1 g.).Reflux gently with stirring under acetylene for 3 hours then let standat room temperature overnight. Pour the reaction into 20% ammoniumchloride solution and extract with ethyl acetate. Wash, dry andevaporate the extract in vacuo. Crystallize the title product from ethylacetate, M.P. -145 C.

For the substrate in the above experiment, substitute a! 3,3ethylenedioxy-l6a-hydroxy-13-ethyl-5a-gon-17- one, formate to obtaindl-3,3-ethylenedioxy-13-ethyl-17aethynyl-5u-gona-160:,17fl-di01.

EXAMPLE 8 dl-16a,17B-dihydroxy-13-ethyl-17a-ethynyl-5fi-gon-3-one Add dl3,3 ethylenedioxy-13-ethyl-l7a-ethynyl-5 3- gona-16a,17;8-diol (325 mg.)to a mixture of methanol (6 ml.), hydrochloric acid (0.2 ml.) and water(0.5 ml.) and stir for 1 /2 hours. Add water and extract with ethylacetate. Wash, dry and evaporate the extract in vacuo to obtain thetitle product as a white solid, yield 180 mg., M.P. 189-194 C.

For the substrate in the above recation substitute dl- 3,3 ethylenedioxy13 ethyl 17a-ethynyl-5a-gona- 16a,17/3 diol to obtain dl16a,17B-dihydroxy-13-ethyl- 17a-ethynyl-5-a-gon-3-one.

EXAMPLE 9 dl-3,3-ethylenedioxy-16a-hydroxy-13-ethyl-5/3-gon-17-one Coola solution of sodium hydroxide (0.2 g.) in methanol 15 ml.) to 5 to 10C. Add dl-3,3-ethylenedioxy 16a-hydroxy-13-ethyl-5B-gon-17-one, formate(500 mg.) and stir for one hour. Add 100 ml. of cold saturated ammoniumchloride solution dropwise. Filter the precipitate and partition itbetween water and choloroform. Wash, dry and evaporate the chloroformlayer to obtain the crystalline title compound, M.P. 190194.

For the substrate above, substitute dl-3,3-ethylenedioxy16a-hydroxy-13-ethyl-5a-gon-l7-one, formate to obtain all 3,3ethylenedioxy- 16a-hydroxy-13-ethyl-5agon-17-one.

EXAMPLE 10 dl-3,3-ethylenedioxy-16a(tetrahydropyran-Z-yloxy) -13-ethyl-5 3-gon-17-one Add dl 3,3ethylenedioxy-16u-hydr0xy-13-ethyl-5figon-17-one (960 mg.) to a mixtureof dry tetrahydro furan (5 ml.) purified dihydropyran (7 ml.) andparatoluene sulfonic acid (15 mg.). Warm the mixture to 40 and stir forone hour, adding a few crystals of paratoluene sulfonic acid. Add sodiumbicarbonate solution (10 ml.). Evaporate the organic solvent in vacuo.Extract the residue with ethyl acetate, wash, dry, and evaporate theextract. Obtain the title compound as a crystalline product from ethylacetate, M.P. 164-166 C.

For the above substrate, in Example 10, substitute dl- 3,3 ethylenedioxy16a-hydroxy-13-ethyl-5u-gon-17-0ne to obtain dl 3,3ethylenedioxy-16a(tetrahydropyran-2- yloxy)-13-ethyl-5a-gon-17-one.

EXAMPLE l1 Equip a flask with a condenser, a magnetic stirrer and a gasinlet tube. Dissolve the 3,3 ethylenedioxy-16a- (tetrahydropyran2-yloxy)-13-ethyl-5fl-gon-17-0ne (400 mg.) in dry benzene (4.0 ml.),dilute the solution with dry dimethyl sulfoxide (10 ml.), pass purifiedacetylene gas into the solution and stir for one hour. Add lithiumacetylide ethylenediamine complex (0.5 g.) and stir for 1.5 hours. Thenadd another 1.5 g. of complex and stir for 1 hour. Pour the mixture intoice water. Extract with ethyl acetate, wash, dry and evaporate theextract in vacuo to obtain the title product.

For the above substrate substitute dl-3,3-ethylenedioxy-16a(tetrahydropyran 2 yloxy) 13-ethyl-5a-gon-17-one to obtain all 3,3ethylenedioxy-16}9(tetrahydropyran-2-yloxy)-13-ethyl-17u-ethynyl-5a-gon-175-01.

EXAMPLE 12 dl-16/i,17 8-dihydroxy-13-ethyl-17a-ethynyl-5 8-gon-3-one Adddl-3,3-ethylenedioxy 165(tetrahydropyran-Z-yloxy)-13-ethyl-17a-ethynyl-5/3-gon-175-01 (300 mg.)to 10 ml. of a solution of concentrated hydrochloric acid (3.2 ml.) inmethanol (100 ml.) and stir for two hours. Add water and extract withethyl acetate. Wash, dry and evaporate the extract in vacuo to obtainthe title compound.

For the above substrate substitutedl-3,3-ethylenedioxy-16;8(tetrahydropyran-Z-yloxy)-13-ethyl 17aethynyl-u-g0n-17fi-ol to obtaindl-16,9,17,9-dihydroxy-l3-ethyl-17a-ethynyl-5a-gon-3-one.

Add sodium borohydride (36 mg.) to a solution of di-16a,17;3-dihydroxy-13-ethyl-17a-ethynyl-5/8-gon-3-one (90 EXAMPLE 14dl-l3-ethyl-17a-ethynyl-5B-gona-3a,16a,17fl-triol Dissolvenil-16a,17fi-dihydroxy-13-ethyl-17u-ethynyl-5figon-3-one mg.) inmethanol (6 ml.) containing nitromethane (1.2 ml.). Add sodiumborohydride and stir for 30 minutes. Add water and obtain a whiteprecipitate. Extract with ethyl acetate, wash, dry and evaporate theextract in vacuo and obtain the title compound. Recrystallize from ethylacetate-isopropanol, M.P. 173174 C.

The subject matter which the applicants regard as their invention isparticularly pointed out and distinctly claimed as follows:

1. A compound of the structure on VX-CECH Mon wherein R is alkyl of from1 to 4 carbon atoms; and X is (3:0,

References Cited UNITED STATES PATENTS 8/1967 Engelfried et a1. 260397.59/1967 Farkas 260-3973 HENRY A. FRENCH, Primary Examiner US. Cl. X.R.

